Public Health

Akiko Iwasaki on what causes long COVID, brain fog, the Yale Paxlovid study and long COVID treatments


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What causes long COVID? Is long COVID dangerous? Who is most likely to get long COVID? Any pediatric long COVID news? What can be done for long term COVID?

Our guest is Akiko Iwasaki, PhD, Sterling Professor of Immunobiology at Yale University. AMA Chief Experience Officer Todd Unger hosts.


  • Akiko Iwasaki, PhD, Sterling Professor of Immunobiology, Yale University

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Unger: Hello and welcome to the AMA Update video and podcast. Today, we're checking in on the latest long COVID research with Dr. Akiko Iwasaki, the Sterling Professor of Immunobiology at Yale University in New Haven, Connecticut. I'm Todd Unger, AMA's chief experience officer in Chicago. Dr. Iwasaki, it's great to see you and good to have you back.

Dr. Iwasaki: I'm delighted to be back. Thank you.

Unger: Well, first off, before we get going, important news. You've been named as one of the top 100 most influential people by Time Magazine. I just want to say congratulations. What a huge achievement.

Dr. Iwasaki: Thank you so much. It's really an honor.

Unger: Well and quite deserved for all the hard work. Of course, so many people still suffering from long COVID and so much work to do. So let's get right into it. Dr. Iwasaki, more studies have come out on the cause of long COVID since we last talked. You've had a number of years of research into the topic. And we'd love to start with some of your current hypotheses on the origins of long COVID.

Dr. Iwasaki: Yes, I'm happy to talk about that. So broadly speaking, there are four different hypotheses that we've been pursuing. And for all of them, there are more and more mounting evidence.

So the number one is the persistent viral replication or remnants of virus antigen and/or RNA hidden away in tissues that are causing chronic inflammation. And there are numerous reports of biopsies and autopsies now showing that viral RNA and protein can be found in a number of different tissues. And they're usually hidden in deeper tissues that are not accessible by nasopharyngeal swabs or even blood sampling. However, there are some recent research showing that there is circulating spike proteins that can be detected in people with long COVID, suggesting that there may be a blood test that we can implement in the future to detect these things.

Second hypothesis is on autoimmunity. So this is, you know, autoimmunity is basically T cells and B cells that are now recognizing host proteins or host antigens as something to attack. And that can happen with respect to—following multiple different types of stresses, including acute infection with SARS-COV-2. And so when that autoimmune response starts to happen, it's very hard to stop them because these antigens are everywhere and they're not going anywhere. So that results in damage of the target organs and other issues that are associated with the immune attack.

The third hypothesis is the reactivation of dormant viruses, such as herpes virus family members. So humans live with many different viruses that are latent. And these are viruses that hide in different tissues. And normally people don't feel anything.

However, during an acute infection or stress, these types of latent viruses can become reactivated. And once that happens, immune responses are also activated. And we have seen evidence, for instance, of Epstein-Barr virus and varicella zoster virus reactivating in people with long COVID. That reactivated virus itself may be triggering some of the symptoms.

And the last hypothesis that people have been looking at is the sort of changing tissue inflammation status resulting from the acute phase of the COVID. So COVID-19 can impact multiple different tissues. For instance, we find that even a mild respiratory infection can trigger changes in the microglia, which are the macrophages of the brain, in a chronic manner that can't be restored back to homeostatic status.

And that results in changes that are consistent with brain fog and neurocognitive dysfunction. So these are four hypotheses for which there are many, many now examples and evidence that's mounting in both human and animal research. And that once we understand these things, there are paths with which we can target these underlying causes.

Unger: So those are big findings. And I'll just see if I can summarize the four that you talked about. Again, kind of persistent infection that may be tough to detect through standard testing, through nasal swabs, autoimmune reactions that are tough to stop once they start, reactivating latent viruses on top of the COVID response, and then this kind of inflammation that has kind of permanent effects that can't just be stopped by themselves.

So that kind of understanding, obviously a huge step forward. Let me just talk to you about that first one you mentioned in that list that maybe then that could lead us to the ability to test for—or to detect that with a test that might not otherwise have been detectable with current testing. I guess I'm not articulating that very well, but is that where you think that could be heading?

Dr. Iwasaki: Right, so there are groups like David Walt's group at Harvard who is using a very sensitive assay to detect viral proteins like the spike and nucleocapsid proteins. And they are finding these in people—blood of people who have long COVID. There is also some detection of people who have recovered from COVID. And so the sensitivity and sort of ability of these kinds of assay to really dissect people who have long COVID versus who don't, it's still not clear.

And also, you know, whether these are actually causing the disease itself or it's just sort of a reflection of the disease. So by targeting these viruses with antibodies or antivirals, you know, whether that would have an impact or not, those are the things that I think we need to be looking at next.

Unger: And, again, having an understanding of the whys here, of course, could be important in terms of the eventual research into treatments. And I know that is going to take a while, but that work is underway. And in fact, your team is running a clinical trial that looks at Paxlovid and long COVID. Any updates on that?

Dr. Iwasaki: Yes, so this is a trial that Dr. Harlan Krumholz is heading at Yale through the Yale LISTEN study. And we have—I'm delighted to tell you that we have completed the enrollment for the Yale Paxlovid study. So the goal of this randomized clinical trials, which involves 100 people with long COVID, which is randomized into 50 in the Paxlovid group and 50 in the placebo arm.

The goal is to really understand whether these 15-day course of Paxlovid is beneficial to people with long COVID. And if so, what are the biomarkers associated with such benefit? So my team is really involved in the latter part of the question, of whether we can identify biomarkers that can predict benefit from Paxlovid. And if we can find such markers, we can then in the future, you know, treat people with those biomarkers with Paxlovid with a better success than those without it.

Unger: Now, another area of research is looking at how to reduce the risk of developing long COVID in the first place. And studies have explored if vaccination plays a role or if drugs like Paxlovid, like we were just talking about, can help not only with treatment, but also with prevention. Have those studies shown anything so far?

Dr. Iwasaki: Yes so there have been many studies that are now looking at what, during the acute phase of COVID, can we do to reduce the risk of developing long COVID? And so vaccination appears to be, you know, repeatedly show—multiple studies showed that vaccinations can reduce that risk prior to getting the infection. And it may even be dose-dependent. So the booster doses are also going to be important in preventing the risk for long COVID.

Evidence for treatment with Paxlovid during the acute phase is a little bit mixed. So the earlier study by Dr. Ziyad Al-Aly showed that Paxlovid treatment for acute COVID is effective in preventing long COVID in high-risk unvaccinated individuals. A recent study by a UCSF group found that in vaccinated non-hospitalized individuals during the first COVID, the use of Paxlovid did not show any effectiveness in reducing the rate of long COVID. So I think it depends on the, you know, the group that we're talking about. But so that is a little bit mixed findings so far.

Unger: All right, well, thank you for that update. And of course, a lot of people out there who once contract COVID, obviously, experiencing issues around COVID, long COVID. In fact, according to the latest data from the CDC, it's about 3 in 10 adults who've had COVID reported getting long COVID. Do we know if the likelihood of developing long COVID is higher or lower with the latest variant?

Dr. Iwasaki: That's a great question. So there are several studies now looking at this issue. A nice case control observational study from the UK has shown that the risk of getting long COVID after Omicron period is about half of that compared to the Delta period. Another study in the U.S. estimates about 1 in 10 adults getting long COVID after the Omicron phase.

So the risk of developing long COVID per infection appears to be lower with the current Omicron variant. However, a lot more people got infected with Omicron and are—continue to be infected on a daily basis, leading to millions of people developing long COVID. So we still cannot really put down our guards with respect to prevention.

Unger: All right, Dr. Iwasaki, a lot of the research that we talk about is about long COVID in adults. But what do physicians and patients need to know about the risk of kids getting long COVID?

Dr. Iwasaki: Yeah, so this is an area that's not well discussed, I think, in public. But an estimated 6 million children are affected by long COVID in the U.S. Children also suffer from similar types of symptoms that are reported for adults with long COVID, but they may not be able to articulate it in the same way that adults might be able to.

And some of the risk factors for pediatric long COVID has been studied and which includes severity of disease. So the more severe the acute phase of COVID, the more likely a child might get long COVID. Increased age group, so teenage years are more at higher risk than younger children. Female sex is also a risk factor in children and underlying conditions like asthma.

Unger: Dr. Iwasaki, thank you so much for joining us again. We have so much viewer response from your prior segments. Clearly, a lot of demand to stay updated. And there's obviously so much more to learn. Again, congratulations on your recognition by the Time 100. How great to see such important work recognized.

Dr. Iwasaki: Thank you so much, Todd. It's such an honor for me and my team.

Unger: For our viewers and listeners out there, if you found this discussion valuable, you can support more programming like it by becoming an AMA member at That's it for today's episode. And we'll be back soon with another AMA Update.

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Disclaimer: The viewpoints expressed in this video are those of the participants and/or do not necessarily reflect the views and policies of the AMA.

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